Method for treating benign prostatic hyperplasia

a benign prostatic hyperplasia and treatment method technology, applied in the field of benign prostatic hyperplasia treatment, can solve the problems of its natural ability to induce hypercalcemia and hyperphosphatemia, and achieve the effects of reducing prostate size, preventing and/or treating bladder dysfunction, and reducing prostate siz

Inactive Publication Date: 2008-02-19
BIOXELL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0015]significantly reduces the growth of human BPH cells in vitro via induction of their apoptosis and reduces prostatic growth in vivo, with no effects on testosterone and dihydrotestosterone levels. Furthermore, this inhibition of prostate growth is achieved at non-hypercalcemic doses. Thus, Compound A is an effective pharmacologic agent for the treatment of benign prostatic hyperplasia.
[0016]As described in the Examples herein, Compound A reduces prostate size. Furthermore, as observed with finasteride, Compound A counteracts against the in vitro and in vivo proliferative activity of testosterone. Significantly however, and unlike finasteride, Compound A does not inhibit type-1 or type-2 5 alpha-reductase activity and can counteract not only testosterone but even dihydrotestosterone induced BPH cell growth. These anti-androgenic properties of Compound A are independent from interaction with the AR, as shown by the failure of Compound A both to bind to the AR, or to act as an AR agonist or antagonist. Furthermore, Compound A does not affect sex hormone secretion. Furthermore, in our studies, Compound A has no significant effect on PSA levels thus there appears to be no danger of treatment with Compound A masking this important indicator of possible prostate cancer.
[0017]A further significant advantage of Compound A is that in vitro studies have revealed that this drug, unlike finasteride, is capable of inhibiting the basal and testosterone-stimulated growth of bladder cells and is expected to be useful in preventing and / or treating of bladder dysfunction in humans. In vivo studies in a validated rat bladder outlet obstruction model of bladder dysfunction have also demonstrated the beneficial effect of Compound A. This is significant because bladder dysfunction is a common and troublesome sequela of BPH. Thus Compound A is capable of reducing prostate size and ameliorating bladder dysfunction, i.e., improving bladder function and bladder related symptoms of BPH at the same time through direct effect of Compound A both on the prostate and on the bladder. This effect is expected to go beyond the improvement in bladder symptoms that would be expected merely as a result of prostate size reduction. Bladder symptoms include overactive bladder and indicators of improved bladder function include reduction in non-voiding contractions and residual urine.

Problems solved by technology

However, a problem with the therapeutic use of calcitriol is its natural ability to induce hypercalcemia and hyperphosphatemia.

Method used

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  • Method for treating benign prostatic hyperplasia
  • Method for treating benign prostatic hyperplasia
  • Method for treating benign prostatic hyperplasia

Examples

Experimental program
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Effect test

example 1

Effects of Compound A on BPH Cells in vitro

Material and Methods

Materials

[0081]Minimum Essential Medium (MEM), DMEM-F12 1:1 mixture, Ham's F12 medium, phosphate buffered saline (PBS), bovine serum albumin (BSA) fraction V, glutamine, geneticine, collagenase type IV, vitamin D3, testosterone (T), dihydrotestosterone (DHT), cyproterone acetate, β-nicotinamide adenine dinucleotide 3′-phosphate reduced form (NADPH), dithithreitol (DTT), phenylmethylsulfonyl fluoride (PMSF) and a kit for measuring calcemia were purchased from Sigma (St. Louis, Mo.). The protein measurement kit was from Bio-Rad Laboratories, Inc. (Hercules, Calif.). Fetal bovine serum (FBS) was purchased from Unipath (Bedford, UK). Monoclonal anti-rat clusterin antibody (mouse monoclonal IgG) specific for beta-chain was from UPSTATE Biotechnology (Lake Placid, N.Y.). Apop Tag kit for in situ end labelling (ISEL) was from Oncor (MD, USA). CHO 1827 and CHO 1829 were provided by Serono International (Geneva, Switzerland). Ins...

example 2

Anti-proliferative Properties of Compound A in in vivo Models of Prostate Growth

Animal Protocols

[0102]Male Sprague Dawley rats (28 days old) were purchased from Charles River Laboratories (Calco, Lecco, Italy). All animal experimentation described was conducted in accord with accepted standards of animal care. Castration was performed via the scrotal route under ketamine / xylazine anaesthesia. Three days after castration, rats (5-8 animals per group) were treated or not with T enanthate (30 mg / Kg) in two separate weekly sc injections. Rats were orally treated for 5 days the first week, and 4 days the second week with vehicle (Miyglyol 812), Compound A (10, 30, 100 and 300 μg / Kg) or finasteride (10 and 40 mg / Kg) for a total of 9 administrations, and sacrificed one day later.

[0103]Alternatively, intact, adult male Sprague Dawley rats (weight 250 g) were dosed orally with vehicle (Miglyol 812), Compound A (10, 30, 100 and 300 μg / Kg) or finasteride (10 and 40 mg / Kg) 5 days / week for 5 con...

example 3

Reduction of Prostate Weight in Healthy Dogs Treated with Compound A

[0120]A 9-month toxicity study was carried out in four groups of male beagle dogs, which were treated by daily oral gavage with 0.5 μg, 1.5 μg and 5 μg / kg body weight / day of Compound A (in vehicle Miglyol 812) or with vehicle alone. This treatment was followed by a 2-month recovery period for the group receiving the highest dose, 5 μg, after which prostate weights was measured. In addition to entirely favourable toxicity data, a lower prostate weight was observed at the end of treatment with Compound A (see FIG. 8) and after recovery (see FIG. 9). The results after recovery were analysed statistically via a one-tailed Student's t test and were found to be significantly different between Compound A and vehicle (P<0.05). These results further demonstrate the ability of Compound A to reduce prostate size in vivo.

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Abstract

The use of 1-alpha-fluoro-25-hydroxy-16,23E-diene-26,27-bishomo-20-epi-cholecalciferol, or a pharmaceutically acceptable salt or ester thereof, for the manufacture of a medicament for the prevention and / or treatment of benign prostatic hyperplasia (BPH) and associated symptoms.

Description

RELATED APPLICATIONS[0001]This application claims priority to GB 0322395.5, filed Sep. 24, 2003, and to GB 0325598.1, filed Nov. 3, 2003, both of which applications are incorporated herein in their entireties by this reference.FIELD OF THE INVENTION[0002]The present invention is concerned with the use of 1-alpha-fluoro-25-hydroxy-16,23E-diene-26,27-bishomo-20-epi-cholecalciferol (Compound A) for the manufacture of a medicament for the prevention and / or treatment of benign prostatic hyperplasia (BPH) and associated symptoms. It is further concerned with a method for preventing and / or treating benign prostatic hyperplasia and associated symptoms by administering 1-alpha-fluoro-25-hydroxy-16,23E-diene-26,27-bishomo-20-epi-cholecalciferol in an amount effective to prevent and / or to treat such disease alone or in combination with further active agents.BACKGROUND OF THE INVENTION[0003]BPH is a common disorder in elderly men, occurring in approximately 50% of men aged 60 years and in 90% o...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/593A61K31/59
CPCA61K31/593A61P13/06A61P13/08
Inventor ADORINI, LUCIANOCOLLI, ENRICO
Owner BIOXELL
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